Sustained release of hydrochlorothiazide

ABSTRACT

A sustained release pharmaceutical composition which includes hydrochlorothiazide and a polymer of a monomer mixture of a monoester of acrylic acid and/or methacrylic acid and a polyhydric alcohol; sulfur containing compound; and a diester of acrylic and/or methacrylic acid.

United States Patent Cohen et al.

I SUSTAINED RELEASE OF HYDROCHLOROTHIAZIDE [75] Inventors: Arthur 1.Cohen; James S. Y. Sim;

Maurice H. Van Horn; Stanley E. Gordesky; Stanley I. Gordon, all ofRochester, NY.

[73] Assignee: Union Corporation, Verona, Pa.

[22] Filed: Sept. 10, 1973 [21] Appl. No.: 395,689

[52] U5. Cl 424/22; 424/81 [51] Int. Cl 4 I A A6lk 27/12 [58] Field ofSearch 424/19-22, 424/81 [56] References Cited UNITED STATES PATENTS3.331.798 7/1967 Hibbard... 260/291) 3.432,4S4 3/1969 Hihhard 260/296Klimcnl et al. 424/21 3,577,512 5/1971 Shepherd et a1 424/21 3,689,6349/1972 Klimcnt et al. I 424/21 3,775,537 11/1973 Lehman et a1, 424/21OTHER PUBLICATIONS Stechor et al., Merck Index 8th Ed., 1968, Merck &Co., Rahwuy, N. l., pp. 541, entry Hydrochlorothiazide."

Primary Examiner$hep K. Rose Attorney Agent, or Firm-Poll0ck, Philpitt &Vunde Sande l 57 1 ABSTRACT I8 Claims, No Drawings SUSTAIN ED RELEASE OFHYDROCHLOROTHIAZIDE BACKGROUND OF THE INVENTION The present invention isconcerned with a sustained release pharmaceutical composition, and inparticular is concerned with a sustained release pharmaceuticalcomposition which contains a water-insoluble but water-swellablehydrophilic polymer of a monomeric mixture containing a monoester ofacrylic and/or methacrylic acid; sulfur containing compounds; and adiester of acrylic and/or methacrylic acid.

It has previously been suggested to incorporate drugs into hydrophilicpolymers to provide sustained release of the drug. Although a widevariety of suitable polymers and applicable drugs have previously beensuggested, only a very limited number of combinations of particulardrugs and particular polymers have to date been successful in providingsustained release characteristics. In addition, various combinationswhich provide sustained release require mixtures of substituents incombination with the drug.

It has become quite evident that not any combination of any drug and anyhydrophilic polymer will provide a sustained release pharmaceuticalcomposition. The preparation of sustained release pharmaceuticalcompositions from polymers and drugs is highly empirical. The art hasnot advanced to the stage where a person skilled in the art can predictwhether a particular combination of a drug and hydrophilic polymer willproduce a sustained release pharmaceutical composition.

Accordingly, it is an object of the present invention to provide asuitable sustained release pharmaceutical composition. It is a furtherobject of the present invention to provide a sustained releasepharmaceutical composition which requires only the pharmacologicalmaterial and the hydrophilic polymer and does not require the presenceof auxiliary constituents and particularly additional polymers.

SUMMARY OF THE INVENTION The present invention is concerned with asustained release pharmaceutical composition comprising:

A. a matrix of a water-insoluble but waterswellable hydrophilic polymerof a monomer mixture containing:

l. polymerizable monoester of acrylic and/or methacrylic acid and apolyhydric alcohol;

2. a polymerizable sulfur containing material selected from the group ofpolymerizable ethylenically unsaturated organic sulfonic acids; ammoniumsalts thereof; alkali metal salts thereof; and mixtures thereof; and

3. diester of acrylic acid and/onrnethacrylic acid and a polyhydricalcohol;

wherein the monomer mixture contains from about 25 to about 94.5% byweight of( l from about to about 45% by weight of(2); and from about 0.5to about 40% by weight of(3) based upon the total weight of( l (2) and(3) in the monomer mixture; and

B. hydrochlorothiazide in an amount at least sufficient for the totaldosage requirement during a treatment period; and being entrapped insaid matrix.

DESCRIPTION OF PREFERRED EMBODIMENTS The polymerizable monoesters whichare suitable in obtaining the polymers employed in the present invention must be water-miscible. Such polymerizable monoesters aremonoesters of either acrylic and/or methacrylic acid and a polyhydricalcohol and preferably a dihydric alcohol. Suitable dihydric alcoholswhich may be employed to form the esters used in the present inventioninclude among others ethylene glycol. 1,3- propanediol, the dialkyleneglycols such as diethylene glycol and dipropylene glycol; and thepolyalkylene glycols such as polyethylene glycol and polypropylereglycol; 1,6-hexamethylene glycol; and l,4-butanediol. Some suitablepolyhydric alcohols which contain from 2 to 6 alcohol groups and whichmay be employed to form the ester used in the present invention includeglycerol, trimethylol propane, trimethylolethane, pentaerythritol, andhexitols such as mannitol and sorbitol. Examples of some suitablepolymerizable monoesters include 2-hydroxy ethyl methacrylate, Z-hydroxyethyl acrylate. 2-hydroxy propyl methacrylate, diethylene glycolmonomethacrylate, diethylene glycol monoacrylate, Z-hydroxy propylacrylate, 3-hydroxy propyl methacrylate, 3-hydroxy propyl acrylate,dipropylene glycol monomethacrylate, glyceryl methacrylate, andpentaerythritol methacrylate, with the preferred polymerizable monoesterbeing 2-hydroxy ethyl methacrylate. The amount of polymerizablemonoester employed in the monomeric mixture to prepare the polymers ofthe present invention is usually from about 25 to about 94.5% by weight,and is preferably from about 35 to about 90% by weight, based upon thetotal weight of the polymerizable monoester, sulfur containing monomer,and diester. The most preferred amount of monoester is between about 40and about by weight based upon the total weight of the monoester, sulfurcontaining monomer, and diester.

The polymerizable sulfur containing material, employed in the polymersof the inner matrix include polymerizable ethylenically unsaturatedorganic sulfonic acids and/or ammonium salts thereof and/or alkali metalsalts thereof such as sodium and potassium salts thereof. Illustrativeof some polymerizable ethylenically unsaturated organic sulfonic acidsinclude vinylsulfonic acid, vinylpropanesulfonic acid, andstyrenesulfonic acids such as p-vinylbenzenesulfonic acid. The preferredacid is p-vinylbenzenesulfonic acid and the preferred polymerizablesulfur containing material is sodium p-vinylbenzenesulfonate.

The amount of polymerizable sulfur containing material is usuallybetween about 5 and about 45% by weight, and is preferably between about5 and 40% by weight, and is most preferably between about 10 and about30% by weight based upon the total weight of the monoester, sulfurcontaining material and diester in the monomer mixture.

The polymerizable diesters employed in the present invention arediesters of acrylic and/or methacrylic acid and a polyhydric alcohol andpreferably a dihydric alcohol. Illustrative of such diesters areethylene glycol diacrylate, ethylene glycol dimethacrylate, 1,2-butylene dimethacrylate, 1,3-butylene dimethacrylate. l,4-butylenedimethacrylate, propylene glycol diacrylate, propylene glycoldimethacrylate, diethylene glycol dimethacrylate, dipropylene glycoldimethacrylate, di' ethylene glycol diacrylate, dipropylene glycoldiacry- Iate, tetraethylene glycol dimethacrylate. and tetramethyleneglycol diacrylate. The preferred diester is tetraethylene glycoldimethacrylate. The amount of diester employed is usually between about0.5 and about 40%, preferably between about 1 and 30%, and mostpreferably between about 5 and about 25.5% by weight based upon thetotal weight of the monocster, sulfur containing monomer and diester.The monomer mixture for obtaining polymers employed according to thepresent invention can contain from about or from about or from about toabout 73.6% by weight of the polymerizable monoester; from about 5 orfrom about It) to about 20% by weight of the polymerizablesulfur-containing material; and from about 0. l or from about 1 or fromabout 5 to about 6?! by weight of the polymerizable diester based uponthe total weight of the polymerizable monoester, polymerizablesulfurcontaining material, and polymerizable diester in the monomermixture.

Hydrochlorothiazide, which is the drug employed according to the presentinvention, is generally used in amounts of about 0.1 to about preferablyfrom about 0.1 to about 35% and most preferably from about 0.5 to about20% by weight based upon the total weight of the hydrochlorothiazide andthe waterinsoluble but water-swellable hydrophilic polymer. Thewater-insoluble but water-swellable hydrophilic poly mer is generallyemployed in amounts of about 50 to about 99.9%, preferably from about toabout 99.9% by weight, and most preferably from about to about 99.5% byweight based upon the total weight of the hydrochlorothiazide andwater-insoluble but waterswellable hydrophilic polymer.

In addition, the pharmaceutical compositions of the present inventioncan include such other materials as plasticizers, inert fillers, andsuspending aids for the hy drochlorothiazide such as Cab-O-Sil andbentone.

Moreover, the compositions of the present invention can be furtherencapsulated by another polymeric or other film-forming substanceaccording to particular applications of the composition. Such auxiliaryencapsulating layers can be soluble or insoluble in aqueous medium, thesolubility or swelling being dependent or independent of pH and/or ionicstrength, and can be susceptible or non-susceptible to enzymatic action.

The pharmaceutical compositions of the present invention can be preparedby admixing the hydrochlorothiazide or an aqueous solution thereof andthe monomeric mixture containing the polymcrizable monoester, sulfurcontaining monomer and diester; and then by polymerizing to provide amatrix of the waterinsoluble but water-swellable polymer entrapping thehydrochlorothiazide.

The pharmaceutical composition of the present invention can also beprepared by contacting the hydrochlorothiazide with the water-insolublebut waterswellahle polymer such as by immersing the polymer in a bathsuch as an aqueous bath of the drug to cause diffusion of thehydrochlorothiazidc into the polymer matrix. Generally thehydrochlorothiazide is contacted with the polymer for at least about 15minutes to cause diffusion into the polymer matrix. Of course. this canvary greatly depending upon the relative amount of the ingredients.

The water-swellablc polymers employed in the present invention generallycan be prepared by employing hulk polymerization techniques The termbulk polymerization as used herein includes those polymerizationscarried out in the absence of a solvent or dispersing liquid as well asthose polymerizations carried out in the presence of water orwatersoluble or polymcr-soluble liquid swelling agents in such amountsas not to significantly alter the nature of the polymerization process.

The polymerization catalyst employed can be any of the catalysts whichare suitable in polymerizing compounds containing ethylcnic unsaturationand preferably are the free radical catalysts. Of particular interestare the peroxide catalysts. Some examples of suitable peroxide catalystsinclude hydrogen peroxide, benzoyl peroxide, tertbutyl peroctoatc,phthalic peroxide, suc cinic peroxide, benzoyl acetic peroxide,tert-butyl peroxy pivalate, coconut oil acid peroxide, lauric peroxide,stearic peroxide, oleic peroxide, tert-butyl hydroperoxide, tetralinehydroperoxide, tert-butyl diperphthalate, cumene hydroperoxide,tert-butyl perbenzoate, acetyl peroxide, 2,4-dichlorobenzoyl peroxide,urea peroxide, caprylyl peroxide, p-chlorobenzoyl peroxide, ditert-butylperoxide, 2,2-bis(tert-butyl peroxy) butane, hydroxyheptyl peroxide, thediperoxide of benzaldehyde', alkylperoxycarbonates such as diisobutylperoxy bicarbonate, di-secondary butyl peroxy bicarbonate, andtert-butyl peroxyisopropylcarbonate, and the like. The preferredcatalyst is one which is effective at moderately low temperatures suchas at about 309()C.

The amount of catalyst employed depends upon the type of catalyst systemused and is generally from about 0.0l to about It) parts by weight per100 parts of the monomer mixture, and preferably is from about 0.1 toabout 1 part by weight per I00 parts of the monomer mixture.

The polymerization is generally carried out at temperatures from aboutroom temperature to about l5llC. It is generally preferred to initiatethe polymerization at relatively low temperatures such as from about 35to about C and then to increase the temperature to about to about C asthe reaction proceeds and preferably after most of the reaction has beencompleted. The most preferred initial temperature range ofpolymerization is between about 30 and 90 C.

Usually the polymerization is conducted under antogenous pressure in aclosed reaction vessel. However, any suitable means to preventsignificant evaporation of any of the monomers can be employed.

Generally, the polymerization is completed in about one-half to about 12hours and preferably is completed in about 4 to about 6 hours. it isunderstood. of course, that the time and temperature are inverselyrelated. That is, temperatures employed at the upper end of thetemperature range will provide polymerization processes which can becompleted near the lower end of the time range.

In addition, it may be desirable for the copolymers obtained from suchpolymerizations to be post cured at temperatures somewhat higher thanthose initially employed in the polymerization. Usually the temperaturesemployed in the post cure will range from about 90 to about l5() C. Twohours is usually more than sufficient for such a post curing operation.Preferably the post cure is completed in 2 to 4 hours.

The pharmaceutical compositions of the present invention can be utilizedfor oral ingestion, implantation, or external application to a mucousmembrane. The pharmaceutical compositions of the present invention canbe implanted subcutaneously, constitute a part of a prosthesis. or beinserted in a cavity of the human body. Upon application to the desiredpart of the body by the desired mode, the pharmaceutical compositions ofthe present invention provide sustained release of the pharmacologicalmaterial by diffusion through pores of the water-insoluble butwater-swellable polymeric matrix to the desired part of the body uponcontact with body fluids.

The present invention makes it possible to obtain a sustained releasepharmaceutical composition which requires only the drug and thewater-insoluble but waterswellable polymer and does not require thepresence of auxiliary polymers. In addition. the sustained releasecharacteristics of the present invention could not be predictedparticularly since the polymers employed in this invention did notalways provide sustained release compositions.

Moreover when hydrochlorothiazide is employed together with otherpolymers, a sustained release composition is not always obtained.

The following example is presented to further illustrate the presentinvention. All parts are by weight unless the contrary is stated.

EXAMPLE I A polymeric composition is prepared by admixing about 28 partsof water and about 100 parts of a polymerizable composition containingabout 73.6% by weight of 2-hydroxy ethyl methacrylate, about by weightof sodium vinylbenzenesulfonate. about 6% by weight of tetraethyleneglycol dimethacrylate; and about 0.4% by weight of tert-butylperoctoate. The mixture is heated to 55 C for about l2 hours under anitrogen atmosphere of 20 psi to effect polymerization.

The mixture is post cured by heating under atmospheric pressure at 80Cfor 2 hours. About 53.72 parts of the resulting polymeric compositionare soaked for about l2 hours at ambient temperature in about 5000 partsof a methanol solution containing 96.2 mg of hydrochlorothiazide per 5ml of methanol solution.

The above composition is introduced into a beaker containing 20milliliters of isotonic saline solution (0.9% NaCl) and the beaker isshaken at a constant temperature of 37 C in a thermostatic water bathshaker. After elution for 3 hours, the composition is removed from thebeaker, dried and then replaced in the beaker and re-eluted. Theconcentration of eluted hydrochlorothiazide is determined with a BeckmanDB-GT spectrophotometer using the maximum absorption ofhydrochlorothiazide at 271 nanometers. Elution rates are checked afterthe initial 3-hour elution period .at the time intervals shown below andfresh isotonic saline solution is employed after such reading. Theresults are listed below.

Time pg of Hydrochlorolhiazide Hours liluted l 224 3 K3 3 49 4 4o 5 27 r23 2 l 2 I 9 I 3 h What is claimed is:

l. A sustained release oral ingestion 23 hour hydrochlorothiazideeluting pharmaceutical composition comprising:

A. a polymerized and cured matrix of water-insoluble but water-swellablehydrophilic polymer of a monomer mixture containing:

l. polymerizable monoester of a member selected from the ;groupconsisting of acrylic acid. methacrylic acid, and mixtures thereof; anda polyhydric alcohol;

2. a polymerizable sulfur containing material selected from the groupconsisting of vinyl sulfonic acid, vinylpropane sulfonic acid, styrenesulfonic acids; alkali metal salts thereof; ammonium salts thereof; andmixtures thereof; and

3. polymerizable diester of a member selected from the group consistingof acrylic acid, methacrylic acid, and mixtures thereof; and apolyhydric alcohol', and

wherein the monomer mixture contains from about 25 to about 73.6% byweight of( l from about 5 to about 20% by weight of 2); and from about0.5 to about 6% by weight of (3) based upon the total weight of (l (2),and (3) in the monomer mixture; and

B. said polymerized and cured matrix having been soaked for about 12hours in methanol solution containing per 5 ml of methanol solution atleast about 96.2 mg of hydrochlorothiazide in an amount sufficient forthe total dosage requirement adapted to gradually elutehydrochlorothiazide upon oral ingestion during 23 hours of a treatmentperiod; and thereby the hydrochlorothiazide being entrapped in saidmatrix.

2. The composition of claim I wherein said polymerizable monoester is amonoester of a member selected from the group consisting of acrylicacid, methacrylic acid, and mixtures thereof; and a polyhydrjc alcoholselected from the group consisting of ethylene glycol. l,3-propanediol,diethylene glycol, dipropylene glycol, polyethylene glycol.polypropylene glycol. 1.6- hexamethylene glycol, 1.4-butanediol.glycerol. trimethylol propane, trimethylolethane, pentaerythritol.mannitol, and sorbitol.

3. The composition of claim I wherein said polymerizable monoester isselected from the group consisting of Z-hydroxy ethyl methacrylate.2-hydroxy ethyl acrylate. Z-hydroxy propyl methacrylate. diethyleneglycol monomethacrylate, diethylene glycol monoacrylate. Z-hydroxypropyl acrylate, Zl-hydroxy propyl methacrylate, 3-hydroxy propylacrylate, dipropylene glycol monomethacrylate, glyceryl methacrylate.and pentaerythritol methacrylate.

4. The composition of claim I wherein said monoester is 2-hydroxy ethylmethacrylate.

5. The composition of claim I wherein said diester is selected from thegroup consisting of ethylene glycol diacrylate. ethylene glycoldimethacrylate. 1.2- butylene dimethacrylate. 1,3-butylenedimethacrylate. l.4-butylene dimethacrylate. propylene glycoldiacrylate. propylene glycol dimethacrylate, diethylene glycoldimethacrylate. dipropylene glycol dimethacrylate. di ethylene glycoldiacrylate, dipropylene glycol diacrylate. tctraethylene glycoldimethacrylate. and tetraethylene glycol diacrylate.

6. The composition of claim 1 wherein said diester is tetraethyleneglycol dimethacrylate.

7. The composition of claim I wherein said polymer izablesulfur-containing material is selected from the group consisting ofstyrene sulfonic acids. ammonium salts thereof. alkali metal saltsthereof; and mixtures thereof.

8. The composition of claim 7 wherein the styrene sulfonic acid isp-toluenc sulfonic acid.

9. The composition of claim I wherein said polymerizablesulfur-containing material is sodium p-toluenc sulfonic acid.

It). The composition of claim I wherein the monomer mixture containsfrom about 35 to about 73.6% by weight of l from about to about 20% byweight of (2); and from about 1 to about 6% by weight of (3) based uponthe total weight of l (2). and (3) in the monomer mixture.

11. The composition of claim 1 wherein the monomer mixture contains fromabout 40 to about 73.6% by weight of (I); from about to about by weightof (2); and from about 5 to about 6% by weight of (3) based upon thetotal weight of l (2), and (3) in the monomer mixture.

12. The composition of claim I wherein (1) said polymerizable monoesteris a monoester of a member selected from the group consisting of acrylicacid methacrylic acid, and mixtures thereof; and a polyhydric alcoholselected from the group consisting of ethylene glycol, 1,3-propanediol.diethylene glycol, dipropylene glycol. polyethylene glycol.polypropylene glycol. L6- hexamethylene glycol, l,4-butanediol,glycerol. trimethylol propane. trimethylolethane, pentaerythritol.mannitol. and sorbitol; wherein said polymerizable sulfur-containingmaterial is selected from the group consisting of styrene sulfonicacids, ammonium salts thereof, alkali metal salts thereof. and mixturesthereof; and wherein said diester (3) is selected from the groupconsisting of ethylene glycol diacrylate. ethylene glycoldimethacrylate, 1,2-butylene dimethacrylate, L3- butylenedimethacrylate, l,4-butylene dimethacrylate, propylene glycoldiacrylate. propylene glycol dimethacrylate, diethylene glycoldimethacrylate, dipropyle'ne glycol dimethacrylate, diethylene glycoldiacrylate, di-

propylene glycol diacrylate. tctracthylcne glycol dimethacrylatc, andtctracthylcne glycol diacrylate.

13. The composition of claim I2 wherein said polyrncrizable monoester isselected from the group consisting of Z-hydroxy ethyl methacrylatc,Z-hydroxy cthyl acrylate. Z-hydroxy propyl mcthacrylatc, dicthyleneglycol monomcthacrylate, diethylene glycol monoacrylate. Z-hydroxypropyl acrylatc. 3-hydroxy propyl methacrylatc, 3hydroxy propylacrylatc. dipro pylcne glycol monomethacrylate. glyceryl methacrylate,and pentaerythritol methacrylate; and wherein the styrene sulfonic acidis p-toluene sulfonic acid.

14. The composition of claim l3 wherein the monomer mixture containsfrom about 35 to about 73.6% by weight of l from about 5 to about 20% byweight of (2); and from about l to about 6% by weight of (3) based uponthe total weight of( l (2). and (3) in the monomer mixture.

15. The composition of claim 4 wherein the mono mer mixture containsfrom about 40 to about 73.6% by weight of l from about l0 to about 20%by weight of(2); and from about 5 to about 671 by weight of 3) basedupon the total weight of l (2). and (3) in the monomer mixture.

16. The composition of claim I wherein said monoester (l) is Z-hydroxyethyl methacrylate; said sulfurcontaining monomer (2) is sodiump-tolucne sullonic acid; and said diester (3) is tctraethylene glycoldimethacrylate.

17. The composition of claim 16 wherein the monomer mixture containsfrom about 35 to about 73.6% by weight of( l from about 5 to about 20%by weight of (2); and from about I to about 6% by weight of (3) basedupon the total weight of( l (2). and (3) in the monomer mixture.

IS. The composition of claim [6 wherein the monomer mixture containsfrom about 40 to about 73.6% by weight of l from about It) to about 20%by weight of (2); and from about 5 to about 6% by weight of 3) monomermixture.

a a: a: a: t

1. A SUSTAINED RELEASE ORAL INGESTION 23 HOUR HYDROCHLOROTHIAZIDEELUTING PHARMACEUTICAL COMPOSITION COMPRISING: A. A POLYMERIZED ANDCURED MATRIX OF WATER-INSOLUBLE BUT WATER-SWELLABLE HYDROPHILIC POLYMEROF A MONOMER MIXTUE CONTAINING:
 1. POLYMERIZABLE MONOESTER OF A MEMBERSELECTED FROM THE GROUP CONSISTING OF ACRYLIC ACID, METHACRYLIC ACID,AND MIXTURES THEREOF, AND A POLYHYDRIC ALCOHOL,
 2. a polymerizablesulfur containing material selected from the group consisting of vinylsulfonic acid, vinylpropane sulfonic acid, styrene sulfonic acids;alkali metal salts thereof; ammonium salts thereof; and mixturesthereof; and
 2. A POLYMERIZABLE SULFUR CONTAINING MATERIAL SELECED FROMTHE GROUP CONSISTING OF VINYL SULFONIC ACID, VINYLPROPANE SULFONIC ACID,STYRENE SULFONIC ACIDS, ALKALI METAL SALTS THEREOF, AMMONIUM SALTSTHEREOF, ANDMIXTURES THEREOF, AND
 2. The composition of claim 1 whereinsaid polymerizable monoester is a monoester of a member selected fromthe group consisting of acrylic acid, methacrylic acid, and mixturesthereof; and a polyhydric alcohol selected from the group consisting ofethylene glycol, 1,3-propanediol, diethylene glycol, dipropylene glycol,polyethylene glycol, polypropylene glycol, 1,6-hexamethylene glycol,1,4-butanediol, glycerol, trimethylol propane, trimethylolethane,pentaerythritol, mannitol, and sorbitol.
 3. The composition of claim 1wherein said polymerizable monoester is selected from the groupconsisting of 2-hydroxy ethyl methacrylate, 2-hydroxy ethyl acrylate,2-hydroxy propyl methacrylate, diethylene glycol monomethacrylate,diethylene glycol monoacrylate, 2-hydroxy propyl acrylate, 3-hydroxypropyl methacrylate, 3-hydroxy propyl acrylate, dipropylene glycolmonomethacrylate, glyceryl methacrylate, and pentaerythritolmethacrylate.
 3. POLYMERIZABLE DIESTER OF A MEMBER SELECTED FROM THEGROUP CONSISTING OF ACRYLIC ACID, METHACRYLIC ACID, AND MIXTURESTHEREOF, AND A POLYHYDRIC ALCOHOL, AND WHEREIN THE MONOMER MIXTURECONTAINS FROM ABOUT 25 TO ABOUT 73.6% BY WEIGHT OF (1), FROM ABOUT 5 TOABOUT 20% BY WEIGHT OF (2), AND FROM ABOUT /.5 T ABOUT 6% BY WEIGHT OF(3) BASED UPON THE TOTAL WEIGHT OF (1), (2), AND (3) IN THE MONOMERMIXTURE, AND B. SAID POLYMERIZED AND CURED MATRIX HAVING BEEN SOAKED FORABOUT 12 HOURS IN METHANOL SOLUTION CONTAINING PER 5 ML OF METHANOLSOLUTION AT LEAST ABOUT 96.2 MG OF HYDROCHLOROTHIAZIDE IN AN AMOUNTSUFFICIENT FOR THE TOTAL DOSAGE REQUIREMENT ADAPTED TO GRADUALLY ELUTEHYDROCHLOROTHIAZIDE UPON ORAL INGESTION DURING 23 HOURS OF A TREATMENTPERIOD, AND THEREBY THE HYDROCHLOROTHIAZIDE BEING ENTRAPPED IN SAIDMATRIX.
 3. polymerizable diester of a member selected from the groupconsisting of acrylic acid, methacrylic acid, and mixtures thereof; anda polyhydric alcohol; and wherein the monomer mixture contains fromabout 25 to about 73.6% by weight of (1); from about 5 to about 20% byweight of (2); and from about 0.5 to about 6% by weight of (3) basedupon the total weight of (1), (2), and (3) in the monomer mixture; andB. said polymerized and cured matrix having been soaked for about 12hours in methanol solution containing per 5 ml of methanol solution atleast about 96.2 mg of hydrochlorothiazide in an amount sufficient forthe total dosage requirement adapted to gradually elutehydrochlorothiazide upon oral ingestion during 23 hours of a treatmentperiod; and thereby the hydrochlorothiazide being entrapped in saidmatrix.
 4. The composition of claim 1 wherein said monoester is2-hydroxy ethyl methacrylate.
 5. The composition of claim 1 wherein saiddiester is selected from the group consisting of ethylene glycoldiacrylate, ethylene glycol dimethacrylate, 1,2-butylene dimethacrylate,1,3-butylene dimethacrylate, 1,4-butylene dimethacrylate, propyleneglycol diacrylate, propylene glycol dimethacrylate, diethylene glycoldimethacrylate, dipropylene glycol dimethacrylate, diethylene glycoldiacrylate, dipropylene glycol diacrylate, tetraethylene glycoldimethacrylate, and tetraethylene glycol diacrylate.
 6. The compositionof claim 1 wherein said diester is tetraethylene glycol dimethacrylate.7. The composition of claim 1 wherein said polymerizablesulfur-containing material is selected from the group consisting ofstyrene sulfonic acids, ammonium salts thereof, alkali metal saltsthereof; and mixtures thereof.
 8. The composition of claim 7 wherein thestyrene sulfonic acid is p-toluene sulfonic acid.
 9. The composition ofclaim 1 wherein said polymerizable sulfur-containing material is sodiump-toluene sulfonic acid.
 10. The composition of claim 1 wherein themonomer mixture contains from about 35 to about 73.6% by weight of (1);from about 5 to about 20% by weight of (2); and from about 1 to about 6%by weight of (3) based upon the total weight of (1), (2), and (3) in themonomer mixture.
 11. The composition of claim 1 wherein the monomermixture contains from about 40 to about 73.6% by weight of (1); fromabout 10 to about 20% by weight of (2); and from about 5 to about 6% byweight of (3) based upon the total weight of (1), (2), and (3) in themonomer mixture.
 12. The composition of claim 1 wherein (1) saidpolymerizable monoester is a monoester of a member selected from thegroup consisting of acrylic acid methacrylic acid, and mixtures thereof;and a polyhydric alcohol selected from the group consisting of ethyleneglycol, 1,3-propanediol, diethylene glycol, dipropylene glycol,polyethylene glycol, polypropylene glycol, 1,6-hexamethylene glycol,1,4-butanediol, glycerol, trimethylol propane, trimethylolethane,pentaerythritol, mannitol, and sorbitol; wherein said polymerizablesulfur-containing material is selected from the group consisting ofstyrene sulfonic acids, ammonium salts thereof, alkali metal saltsthereof, and mixtures thereof; and wherein said diester (3) is selectedfrom the group consisting of ethylene glycol diacrylate, ethylene glycoldimethacrylate, 1,2-butylene dimethacrylate, 1,3-butylenedimethacrylate, 1,4-butylene dimethacrylate, propylene glycoldiacrylate, propylene glycol dimethacrylate, diethylene glycoldimethacrylate, dipropylene glycol dimethacrylate, diethylene glycoldiacrylate, dipropylene glycol diacrylate, tetraethylene glycoldimethacrylate, and tetraethylene glycol diacrylate.
 13. The compositionof claim 12 wherein said polymerizable monoester is selected from thegroup consisting of 2-hydroxy ethyl methacrylate, 2-hydroxy ethylacrylate, 2-hydroxy propyl methacrylate, diethylene glYcolmonomethacrylate, diethylene glycol monoacrylate, 2-hydroxy propylacrylate, 3-hydroxy propyl methacrylate, 3-hydroxy propyl acrylate,dipropylene glycol monomethacrylate, glyceryl methacrylate, andpentaerythritol methacrylate; and wherein the styrene sulfonic acid isp-toluene sulfonic acid.
 14. The composition of claim 13 wherein themonomer mixture contains from about 35 to about 73.6% by weight of (1);from about 5 to about 20% by weight of (2); and from about 1 to about 6%by weight of (3) based upon the total weight of (1), (2), and (3) in themonomer mixture.
 15. The composition of claim 4 wherein the monomermixture contains from about 40 to about 73.6% by weight of (1); fromabout 10 to about 20% by weight of (2); and from about 5 to about 6% byweight of (3) based upon the total weight of (1), (2), and (3) in themonomer mixture.
 16. The composition of claim 1 wherein said monoester(1) is 2-hydroxy ethyl methacrylate; said sulfur-containing monomer (2)is sodium p-toluene sulfonic acid; and said diester (3) is tetraethyleneglycol dimethacrylate.
 17. The composition of claim 16 wherein themonomer mixture contains from about 35 to about 73.6% by weight of (1);from about 5 to about 20% by weight of (2); and from about 1 to about 6%by weight of (3) based upon the total weight of (1), (2), and (3) in themonomer mixture.
 18. The composition of claim 16 wherein the monomermixture contains from about 40 to about 73.6% by weight of (1); fromabout 10 to about 20% by weight of (2); and from about 5 to about 6% byweight of (3) based upon the total weight of (1), (2), and (3) in themonomer mixture.